#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Mismatch Repair Genes and Modify CAG Instability in Huntington's Disease Mice: Genome-Wide and Candidate Approaches


The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease HdhQ111 mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.HdhQ111) than on a 129 background (129.HdhQ111). Linkage mapping in (B6x129).HdhQ111 F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. Crossing B6.HdhQ111 mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. HdhQ111 somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1–MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2–MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1 protein levels play an important role in driving of the efficiency of somatic expansions.


Vyšlo v časopise: Mismatch Repair Genes and Modify CAG Instability in Huntington's Disease Mice: Genome-Wide and Candidate Approaches. PLoS Genet 9(10): e32767. doi:10.1371/journal.pgen.1003930
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003930

Souhrn

The Huntington's disease gene (HTT) CAG repeat mutation undergoes somatic expansion that correlates with pathogenesis. Modifiers of somatic expansion may therefore provide routes for therapies targeting the underlying mutation, an approach that is likely applicable to other trinucleotide repeat diseases. Huntington's disease HdhQ111 mice exhibit higher levels of somatic HTT CAG expansion on a C57BL/6 genetic background (B6.HdhQ111) than on a 129 background (129.HdhQ111). Linkage mapping in (B6x129).HdhQ111 F2 intercross animals identified a single quantitative trait locus underlying the strain-specific difference in expansion in the striatum, implicating mismatch repair (MMR) gene Mlh1 as the most likely candidate modifier. Crossing B6.HdhQ111 mice onto an Mlh1 null background demonstrated that Mlh1 is essential for somatic CAG expansions and that it is an enhancer of nuclear huntingtin accumulation in striatal neurons. HdhQ111 somatic expansion was also abolished in mice deficient in the Mlh3 gene, implicating MutLγ (MLH1–MLH3) complex as a key driver of somatic expansion. Strikingly, Mlh1 and Mlh3 genes encoding MMR effector proteins were as critical to somatic expansion as Msh2 and Msh3 genes encoding DNA mismatch recognition complex MutSβ (MSH2–MSH3). The Mlh1 locus is highly polymorphic between B6 and 129 strains. While we were unable to detect any difference in base-base mismatch or short slipped-repeat repair activity between B6 and 129 MLH1 variants, repair efficiency was MLH1 dose-dependent. MLH1 mRNA and protein levels were significantly decreased in 129 mice compared to B6 mice, consistent with a dose-sensitive MLH1-dependent DNA repair mechanism underlying the somatic expansion difference between these strains. Together, these data identify Mlh1 and Mlh3 as novel critical genetic modifiers of HTT CAG instability, point to Mlh1 genetic variation as the likely source of the instability difference in B6 and 129 strains and suggest that MLH1 protein levels play an important role in driving of the efficiency of somatic expansions.


Zdroje

1. The Huntington's Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72: 971–983.

2. LeeJM, RamosEM, LeeJH, GillisT, MysoreJS, et al. (2012) CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology 78: 690–695.

3. LiJL, HaydenMR, AlmqvistEW, BrinkmanRR, DurrA, et al. (2003) A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study. Am J Hum Genet 73: 682–687.

4. WexlerNS, LorimerJ, PorterJ, GomezF, MoskowitzC, et al. (2004) Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc Natl Acad Sci U S A 101: 3498–3503.

5. GusellaJF, MacDonaldME (2009) Huntington's disease: the case for genetic modifiers. Genome Med 1: 80.

6. DuyaoM, AmbroseC, MyersR, NovellettoA, PersichettiF, et al. (1993) Trinucleotide repeat length instability and age of onset in Huntington's disease. Nature genetics 4: 387–392.

7. KennedyL, EvansE, ChenCM, CravenL, DetloffPJ, et al. (2003) Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum Mol Genet 12: 3359–3367.

8. WheelerVC, PersichettiF, McNeilSM, MysoreJS, MysoreSS, et al. (2007) Factors associated with HD CAG repeat instability in Huntington disease. J Med Genet 44: 695–701.

9. VeitchNJ, EnnisM, McAbneyJP, ShelbournePF, MoncktonDG (2007) Inherited CAG.CTG allele length is a major modifier of somatic mutation length variability in Huntington disease. DNA Repair (Amst) 6: 789–796.

10. GonitelR, MoffittH, SathasivamK, WoodmanB, DetloffPJ, et al. (2008) DNA instability in postmitotic neurons. Proc Natl Acad Sci U S A 105: 3467–3472.

11. SwamiM, HendricksAE, GillisT, MassoodT, MysoreJ, et al. (2009) Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset. Hum Mol Genet 18: 3039–3047.

12. TeleniusH, KremerB, GoldbergYP, TheilmannJ, AndrewSE, et al. (1994) Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm. Nat Genet 6: 409–414.

13. De RooijKE, De Koning GansPA, RoosRA, Van OmmenGJ, Den DunnenJT (1995) Somatic expansion of the (CAG)n repeat in Huntington disease brains. Hum Genet 95: 270–274.

14. KaplanS, ItzkovitzS, ShapiroE (2007) A Universal Mechanism Ties Genotype to Phenotype in Trinucleotide Diseases. PLoS Comput Biol 3: e235.

15. WheelerVC, AuerbachW, WhiteJK, SrinidhiJ, AuerbachA, et al. (1999) Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. Hum Mol Genet 8: 115–122.

16. WheelerVC, WhiteJK, GutekunstCA, VrbanacV, WeaverM, et al. (2000) Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice. Hum Mol Genet 9: 503–513.

17. LloretA, DragilevaE, TeedA, EspinolaJ, FossaleE, et al. (2006) Genetic background modifies nuclear mutant huntingtin accumulation and HD CAG repeat instability in Huntington's disease knock-in mice. Hum Mol Genet 15: 2015–2024.

18. WheelerVC, LebelLA, VrbanacV, TeedA, te RieleH, et al. (2003) Mismatch repair gene Msh2 modifies the timing of early disease in Hdh(Q111) striatum. Hum Mol Genet 12: 273–281.

19. DragilevaE, HendricksA, TeedA, GillisT, LopezET, et al. (2009) Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes. Neurobiol Dis 33: 37–47.

20. KovalenkoM, DragilevaE, St ClaireJ, GillisT, GuideJR, et al. (2012) Msh2 Acts in Medium-Spiny Striatal Neurons as an Enhancer of CAG Instability and Mutant Huntingtin Phenotypes in Huntington's Disease Knock-In Mice. PLoS One 7: e44273.

21. ManleyK, ShirleyTL, FlahertyL, MesserA (1999) Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat Genet 23: 471–473.

22. van den BroekWJ, NelenMR, WansinkDG, CoerwinkelMM, te RieleH, et al. (2002) Somatic expansion behaviour of the (CTG)n repeat in myotonic dystrophy knock-in mice is differentially affected by Msh3 and Msh6 mismatch-repair proteins. Hum Mol Genet 11: 191–198.

23. SavouretC, BrissonE, EssersJ, KanaarR, PastinkA, et al. (2003) CTG repeat instability and size variation timing in DNA repair-deficient mice. EMBO J 22: 2264–2273.

24. Gomes-PereiraM, FortuneMT, IngramL, McAbneyJP, MoncktonDG (2004) Pms2 is a genetic enhancer of trinucleotide CAG.CTG repeat somatic mosaicism: implications for the mechanism of triplet repeat expansion. Hum Mol Genet 13: 1815–1825.

25. OwenBA, YangZ, LaiM, GajecM, BadgerJD2nd, et al. (2005) (CAG)(n)-hairpin DNA binds to Msh2-Msh3 and changes properties of mismatch recognition. Nat Struct Mol Biol 12: 663–670.

26. FoiryL, DongL, SavouretC, HubertL, te RieleH, et al. (2006) Msh3 is a limiting factor in the formation of intergenerational CTG expansions in DM1 transgenic mice. Hum Genet 119: 520–526.

27. TomeS, HoltI, EdelmannW, MorrisGE, MunnichA, et al. (2009) MSH2 ATPase domain mutation affects CTG*CAG repeat instability in transgenic mice. PLoS Genet 5: e1000482.

28. BournRL, De BiaseI, PintoRM, SandiC, Al-MahdawiS, et al. (2012) Pms2 Suppresses Large Expansions of the (GAA.TTC)(n) Sequence in Neuronal Tissues. PLoS One 7: e47085.

29. TomeS, ManleyK, SimardJP, ClarkGW, SleanMM, et al. (2013) MSH3 Polymorphisms and Protein Levels Affect CAG Repeat Instability in Huntington's Disease Mice. PLoS Genet 9: e1003280.

30. Van RaamsdonkJM, MetzlerM, SlowE, PearsonJ, SchwabC, et al. (2007) Phenotypic abnormalities in the YAC128 mouse model of Huntington disease are penetrant on multiple genetic backgrounds and modulated by strain. Neurobiol Dis 26: 189–200.

31. CowinRM, BuiN, GrahamD, GreenJR, Yuva-PaylorLA, et al. (2012) Genetic background modulates behavioral impairments in R6/2 mice and suggests a role for dominant genetic modifiers in Huntington's disease pathogenesis. Mamm Genome 23: 367–377.

32. LeeJM, ZhangJ, SuAI, WalkerJR, WiltshireT, et al. (2010) A novel approach to investigate tissue-specific trinucleotide repeat instability. BMC Syst Biol 4: 29.

33. LeeJM, PintoRM, GillisT, St ClaireJC, WheelerVC (2011) Quantification of Age-Dependent Somatic CAG Repeat Instability in Hdh CAG Knock-In Mice Reveals Different Expansion Dynamics in Striatum and Liver. PLoS One 6: e23647.

34. FlintJ, ValdarW, ShifmanS, MottR (2005) Strategies for mapping and cloning quantitative trait genes in rodents. Nat Rev Genet 6: 271–286.

35. LanderES, BotsteinD (1989) Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121: 185–199.

36. EdelmannW, CohenPE, KaneM, LauK, MorrowB, et al. (1996) Meiotic pachytene arrest in MLH1-deficient mice. Cell 85: 1125–1134.

37. PolosinaYY, CupplesCG (2010) MutL: conducting the cell's response to mismatched and misaligned DNA. Bioessays 32: 51–59.

38. KunkelTA, ErieDA (2005) DNA mismatch repair. Annu Rev Biochem 74: 681–710.

39. LipkinSM, MoensPB, WangV, LenziM, ShanmugarajahD, et al. (2002) Meiotic arrest and aneuploidy in MLH3-deficient mice. Nat Genet 31: 385–390.

40. Flores-RozasH, KolodnerRD (1998) The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent suppression of frameshift mutations. Proc Natl Acad Sci U S A 95: 12404–12409.

41. CharbonneauN, AmunugamaR, SchmutteC, YoderK, FishelR (2009) Evidence that hMLH3 functions primarily in meiosis and in hMSH2-hMSH3 mismatch repair. Cancer Biol Ther 8: 1411–1420.

42. CannavoE, MarraG, Sabates-BellverJ, MenigattiM, LipkinSM, et al. (2005) Expression of the MutL homologue hMLH3 in human cells and its role in DNA mismatch repair. Cancer Res 65: 10759–10766.

43. TomeS, SimardJP, SleanMM, HoltI, MorrisGE, et al. (2013) Tissue-specific mismatch repair protein expression: MSH3 is higher than MSH6 in multiple mouse tissues. DNA Repair (Amst) 12: 46–52.

44. KeaneTM, GoodstadtL, DanecekP, WhiteMA, WongK, et al. (2011) Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 477: 289–294.

45. YalcinB, WongK, AgamA, GoodsonM, KeaneTM, et al. (2011) Sequence-based characterization of structural variation in the mouse genome. Nature 477: 326–329.

46. HallMC, ShcherbakovaPV, KunkelTA (2002) Differential ATP binding and intrinsic ATP hydrolysis by amino-terminal domains of the yeast Mlh1 and Pms1 proteins. J Biol Chem 277: 3673–3679.

47. ConsortiumTU (2012) Reorganizing the protein space at the Universal Protein Resource (UniProt). Nucleic Acids Research 40: D71–D75.

48. AdzhubeiIA, SchmidtS, PeshkinL, RamenskyVE, GerasimovaA, et al. (2010) A method and server for predicting damaging missense mutations. Nat Methods 7: 248–249.

49. ZhangY, YuanF, PresnellSR, TianK, GaoY, et al. (2005) Reconstitution of 5′-directed human mismatch repair in a purified system. Cell 122: 693–705.

50. PanigrahiGB, SleanMM, SimardJP, PearsonCE (2012) Human mismatch repair protein hMutLalpha is required to repair short slipped-DNAs of trinucleotide repeats. J Biol Chem 287 (50) 41844–50.

51. PanigrahiGB, SleanMM, SimardJP, GileadiO, PearsonCE (2010) Isolated short CTG/CAG DNA slip-outs are repaired efficiently by hMutSbeta, but clustered slip-outs are poorly repaired. Proc Natl Acad Sci U S A 107: 12593–12598.

52. KlunglandA, LindahlT (1997) Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for DNase IV (FEN1). EMBO J 16: 3341–3348.

53. CortezD, GuntukuS, QinJ, ElledgeSJ (2001) ATR and ATRIP: partners in checkpoint signaling. Science 294: 1713–1716.

54. GoulaAV, BerquistBR, WilsonDM3rd, WheelerVC, TrottierY, et al. (2009) Stoichiometry of base excision repair proteins correlates with increased somatic CAG instability in striatum over cerebellum In Huntington's disease transgenic mice. PLoS Genet 5: e1000749.

55. GoulaAV, PearsonCE, Della MariaJ, TrottierY, TomkinsonAE, et al. (2012) The nucleotide sequence, DNA damage location, and protein stoichiometry influence the base excision repair outcome at CAG/CTG repeats. Biochemistry 51: 3919–3932.

56. Lopez CastelA, TomkinsonAE, PearsonCE (2009) CTG/CAG repeat instability is modulated by the levels of human DNA ligase I and its interaction with proliferating cell nuclear antigen: a distinction between replication and slipped-DNA repair. J Biol Chem 284: 26631–26645.

57. LiuY, PrasadR, BeardWA, HouEW, HortonJK, et al. (2009) Coordination between polymerase beta and FEN1 can modulate CAG repeat expansion. J Biol Chem 284: 28352–28366.

58. LinY, WilsonJH (2009) Diverse effects of individual mismatch repair components on transcription-induced CAG repeat instability in human cells. DNA Repair (Amst) 8: 878–885.

59. EzzatizadehV, PintoRM, SandiC, SandiM, Al-MahdawiS, et al. (2012) The mismatch repair system protects against intergenerational GAA repeat instability in a Friedreich ataxia mouse model. Neurobiol Dis 46: 165–171.

60. LangWH, CoatsJE, MajkaJ, HuraGL, LinY, et al. (2011) Conformational trapping of mismatch recognition complex MSH2/MSH3 on repair-resistant DNA loops. Proc Natl Acad Sci U S A 108: E837–844.

61. SugawaraN, PaquesF, ColaiacovoM, HaberJE (1997) Role of Saccharomyces cerevisiae Msh2 and Msh3 repair proteins in double-strand break-induced recombination. Proc Natl Acad Sci U S A 94: 9214–9219.

62. KadyrovFA, DzantievL, ConstantinN, ModrichP (2006) Endonucleolytic function of MutLalpha in human mismatch repair. Cell 126: 297–308.

63. PluciennikA, BurdettV, BaitingerC, IyerRR, ShiK, et al. (2013) Extrahelical (CAG)/(CTG) triplet repeat elements support proliferating cell nuclear antigen loading and MutLalpha endonuclease activation. Proc Natl Acad Sci U S A 110: 12277–12282.

64. EdelbrockMA, KaliyaperumalS, WilliamsKJ (2013) Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities. Mutat Res 743–744: 53–66.

65. Pena-DiazJ, JiricnyJ (2012) Mammalian mismatch repair: error-free or error-prone? Trends Biochem Sci 37: 206–214.

66. KolasNK, CohenPE (2004) Novel and diverse functions of the DNA mismatch repair family in mammalian meiosis and recombination. Cytogenet Genome Res 107: 216–231.

67. PengM, LitmanR, XieJ, SharmaS, BroshRMJr, et al. (2007) The FANCJ/MutLalpha interaction is required for correction of the cross-link response in FA-J cells. EMBO J 26: 3238–3249.

68. PolosinaYY, CupplesCG (2010) Wot the 'L-Does MutL do? Mutat Res 705: 228–238.

69. SleanMM, PanigrahiGB, RanumLP, PearsonCE (2008) Mutagenic roles of DNA “repair” proteins in antibody diversity and disease-associated trinucleotide repeat instability. DNA Repair (Amst) 7: 1135–1154.

70. Pena-DiazJ, BregenhornS, GhodgaonkarM, FollonierC, Artola-BoranM, et al. (2012) Noncanonical mismatch repair as a source of genomic instability in human cells. Mol Cell 47: 669–680.

71. ShelbournePF, Keller-McGandyC, BiWL, YoonSR, DubeauL, et al. (2007) Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain. Hum Mol Genet 16: 1133–1142.

72. WeiK, KucherlapatiR, EdelmannW (2002) Mouse models for human DNA mismatch-repair gene defects. Trends Mol Med 8: 346–353.

73. PeltomakiP, VasenH (2004) Mutations associated with HNPCC predisposition – Update of ICG-HNPCC/INSiGHT mutation database. Dis Markers 20: 269–276.

74. ChenPC, DudleyS, HagenW, DizonD, PaxtonL, et al. (2005) Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse. Cancer Res 65: 8662–8670.

75. PlaschkeJ, PreusslerM, ZieglerA, SchackertHK (2012) Aberrant protein expression and frequent allelic loss of MSH3 in colorectal cancer with low-level microsatellite instability. Int J Colorectal Dis 27: 911–919.

76. KovtunIV, LiuY, BjorasM, KlunglandA, WilsonSH, et al. (2007) OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature 447: 447–452.

77. HubertLJr, LinY, DionV, WilsonJH (2011) Xpa deficiency reduces CAG trinucleotide repeat instability in neuronal tissues in a mouse model of SCA1. Hum Mol Genet 20: 4822–4830.

78. MollersenL, RoweAD, IlluzziJL, HildrestrandGA, GerholdKJ, et al. (2012) Neil1 is a genetic modifier of somatic and germline CAG trinucleotide repeat instability in R6/1 mice. Hum Mol Genet 21: 4939–4947.

79. MangiariniL, SathasivamK, MahalA, MottR, SellerM, et al. (1997) Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation. Nat Genet 15: 197–200.

80. KirbyA, KangHM, WadeCM, CotsapasC, KostemE, et al. (2010) Fine mapping in 94 inbred mouse strains using a high-density haplotype resource. Genetics 185: 1081–1095.

81. LanderES, GreenP, AbrahamsonJ, BarlowA, DalyMJ, et al. (1987) MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. Genomics 1: 174–181.

82. PatersonAH, LanderES, HewittJD, PetersonS, LincolnSE, et al. (1988) Resolution of quantitative traits into Mendelian factors by using a complete linkage map of restriction fragment length polymorphisms. Nature 335: 721–726.

83. Lincoln SE, Daly MJ, Lander ES (1993) Constructing Genetic Linkage Maps with MAPMAKER/EXP Version 3.0: A Tutorial and Reference Manual. Whitehead Institute for Biomedical Research Technical Report, 3rd edition.

84. Lincoln SE, Daly MJ, Lander ES (1993) Mapping Genes Controlling Quantitative Traits Using MAPMAKER/QTL Version 1.1: A Tutorial and Reference Manual. Whitehead Institute for Biomedical Research Technical Report, 2nd edition.

85. LanderE, KruglyakL (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11: 241–247.

86. OoijenJ (1992) Accuracy of mapping quantitative trait loci in autogamous species. Theoretical and Applied Genetics 84: 803–811.

87. GutekunstCA, LiSH, YiH, MulroyJS, KuemmerleS, et al. (1999) Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology. J Neurosci 19: 2522–2534.

88. SeongIS, WodaJM, SongJJ, LloretA, AbeyrathnePD, et al. (2010) Huntingtin facilitates polycomb repressive complex 2. Hum Mol Genet 19: 573–583.

89. LiGM, ModrichP (1995) Restoration of mismatch repair to nuclear extracts of H6 colorectal tumor cells by a heterodimer of human MutL homologs. Proc Natl Acad Sci U S A 92: 1950–1954.

90. GammieAE, ErdenizN, BeaverJ, DevlinB, NanjiA, et al. (2007) Functional characterization of pathogenic human MSH2 missense mutations in Saccharomyces cerevisiae. Genetics 177: 707–721.

91. AldredPM, BortsRH (2007) Humanizing mismatch repair in yeast: towards effective identification of hereditary non-polyposis colorectal cancer alleles. Biochem Soc Trans 35: 1525–1528.

92. TakahashiM, ShimodairaH, Andreutti-ZauggC, IggoR, KolodnerRD, et al. (2007) Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Cancer Res 67: 4595–4604.

93. TrojanJ, ZeuzemS, RandolphA, HemmerleC, BriegerA, et al. (2002) Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. Gastroenterology 122: 211–219.

94. PfafflMW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29: e45.

95. TrettelF, RigamontiD, Hilditch-MaguireP, WheelerVC, SharpAH, et al. (2000) Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells. Hum Mol Genet 9: 2799–2809.

96. SieversF, WilmA, DineenD, GibsonTJ, KarplusK, et al. (2011) Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol 7: 539.

97. WaterhouseAM, ProcterJB, MartinDM, ClampM, BartonGJ (2009) Jalview Version 2–a multiple sequence alignment editor and analysis workbench. Bioinformatics 25: 1189–1191.

98. PearsonCE, EwelA, AcharyaS, FishelRA, SindenRR (1997) Human MSH2 binds to trinucleotide repeat DNA structures associated with neurodegenerative diseases. Hum Mol Genet 6: 1117–1123.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2013 Číslo 10
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#